Morphine has been used for centuries to alleviate pain and still remains the analgesic standard to which newly developed drugs are compared. However, prolonged use of morphine, as well as other opiates,, can lead to the development of tolerance, dependence, and ultimately, addiction. Recently, we showed that a G protein-coupled receptor regulatory element, betaarrestin-I, is required for mu opioid receptor (muOR) desensitization in vivo. Mice lacking the Betaarrestin-2 molecule, but not Betaarrestin-I, experience enhanced and prolonged morphine analgesia. Moreover, muOR desensitization proved to be essential in the development of morphine antinociceptive tolerance yet the presence of a functional desensitization mechanism was not required to develop morphine dependence. The dissociation of morphine tolerance and dependence in these mice raises the question whether other manifestations of muOR activation could be differently effected by a loss of Betaarestin-2. Using the Betaarrestin-2-knockout (betaarr2-KO) mice, we have the opportunity to evaluate whether other physiological parameters are subject to tolerance or sensitization after chronic morphine in an animal which lacks tolerance to morphine antinociceptive effects. We anticipate that not all of the physiological functions effected by chronic morphine will experience a change in regulation in the absence of Betaarrestin-2 just as the Betaarr2-KO mice experienced the same degree of morphine dependence as their wild-type littermates. This proposal aims to examine the following questions: AIM I: To test whether morphine tolerance occurs in the suppression of respiration or gastrointestinal transit in mice that lack morphine antinociceptive tolerance. AIM II: To test the effect of chronic morphine on the dopamine system in mice that lack morphine on the dopamine system in mice that lack morphine antinociceptive tolerance. AIM III: To examine the rewarding properties of morphine in mice that lack morphine antinoci ceptive tolerance. My hope is that this research plan will shed light on the role of muOR regulation in mediating the diverse physiological effects that occur with chronic morphine use or abuse. This research proposal has also been designed to direct my scientific development, allowing for the acquisition of diverse experimental approaches to better address the problem of drug abuse in an animal model. By combining the knowledge of systems relating to whole animal physiology, complex animal behaviors, as well as highly intricate neurochemical assessments, I hope to broaden my scientific approach in the pursuit of several independent avenues for my continuing research in the field of drug abuse. I envision that the observation made in the Betaarrestin-2 knockout mice, may lead to greater understanding of the mechanisms behind the potential for developing morphine tolerance, dependence, and addiction following chronic use or abuse.